Procedure for preparing enteric-coated pellets containing a proton pump inhibitor and multi-particle pharmaceutical compositions containing them

ABSTRACT

Pharmaceutical compositions are provided which include enteric-coated pellets. The enteric-coated pellets include pure cellulose cores. A coating is present on the cores which contains 1) a proton pump inhibitor with benzimidazole structure in an amount greater than 10.5% by weight with respect to the total weight of the enteric-coated pellets, 2) one or more of lysine, histidine, and L-arginine, and 3) polyvinylpyrrolidone, wherein the dibasic amino acid is present in an amount less than or equal to 10% by weight in relation to the weight of the proton pump inhibitor. An enteric coating disposed over said coating. Enteric-coated pellets that contain pure cellulose cores having an average diameter between 150 and 300 microns have an average diameter between 350 and 590 microns and the enteric-coated pellets that contain pure cellulose cores with an average diameter between 300 and 500 microns have an average diameter between 500 and 710 microns.

REFERENCE TO RELATED APPLICATIONS

This is a divisional application of U.S. patent application Ser. No.15/563,181, filed Sep. 29, 2017, which is a U.S. national stageapplication of PCT/EP2015/056982, filed Mar. 31, 2015, the entirecontent of both of which is incorporated herein by reference.

FIELD OF THE INVENTION

This invention relates to a procedure for preparing enteric-coatedpellets comprising pure cellulose cores containing on the surfacethereof a substantially uniform distribution of a proton pump inhibitorwith benzimidazole structure together with a dibasic amino acid as theinternal protection agent mainly in an amorphous state, preferablycompletely amorphous, a recrystallisation inhibitor of the dibasic aminoacid and subsequent enteric coating; wherein the contents of the protonpump inhibitor is more than 10.5% and preferably more than 12.0% and theaverage pellet size is less than 710 microns, preferably between 350 and500 microns.

The invention also relates to the multi-particle pharmaceuticalcompositions either in the form of oral disintegration tablets, powderfor suspension or capsules comprising the pellets obtained by theprocess of the invention.

The multi-particle pharmaceutical compositions of the invention have theadvantage that they are not contra-indicated in patients who have“lactose intolerance” or diabetic patients.

The pellets are useful for preparing multi-particle pharmaceuticalcompositions characterized because they are easy to take andparticularly easy to administer to patients who have difficultyswallowing even when their feeding is normal.

BACKGROUND OF THE INVENTION

Oral tablets are the preferred pharmaceutical format and use in humanmedicine.

The preparation of oral tablets has several associated practicalproblems which, since the invention of the first tablet during the1890s, have required searching for specific technological solutionsapplicable to each case and to each particular problem.

So, for example, in the respective technologies developed, subjects ofspecial interest, inter alia, have been, (a) facilitating preparation,(b) masking the taste of the active ingredient they contain (c) ensuringthe stability of the active ingredient vis-à-vis excipients in thetablets and even vis-à-vis the acid medium in the stomach, (d) increasethe bioavailability of the active ingredient, and others, improving theoverall quality of the tablets produced.

In the last two decades some developed technologies have focused onfacilitating tablet swallowing, others on improving the absorption ofthe active ingredient they contain and others on incorporating bothadvantages.

One of the drawbacks observed during the use of tablets in humanmedicine is the frequent difficulty in taking them, mainly in childrenand old-aged patients. The difficulty in taking them is a consequence ofproblems with swallowing due to different causes (psychic or physical),a particularly significant difficulty in patients with dysphagia causedby certain pathologies like Parkinson's disease, neurological problemsor nauseous states.

The difficulty in swallowing also exists among adults who usually haveno drawbacks with their normal feeding. thus, it is highlighted, interalia, as follows:

-   -   a study on a national scale in USA (USA TODAY—The Society for        the Advancement of Education—October 2004) describes that:

a) more than 40% of the adult population has problems in swallowingtablets, even when they have no difficulty swallowing food or drink,

b) that swallowing problems cause: a delay in taking the medicine (14%),missing the dose (8%) or abandoning the treatment (4%).

-   -   Another study in Norway (Anderson o et al (1995)—Tidsskr, Nor        Laegerforen—115, 947-949) carried out on 6158 general medicine        patients revealed that approximately 26% of these patients did        not take the medication prescribed because of problems        associated with swallowing. The problems were linked to the size        of the tablet, its surface or taste.

As is well known, the basis of the success or failure of the therapeutictreatment depends on the continuity of the treatment indicated to thepatient.

In the last decade an alternative for overcoming the drawbacks mentionedwas the increasing development of orodispersable type tablets known bythe FDA under the acronym ODT (Oral Disintegration Tablets).

Such tablets have various advantages:

1) They are easy to administer to adult patients and particularly, togeriatric patients and children.

2) They are particularly useful for administering to patients who arenon-cooperative, disabled, have mental problems or dysphagia conditions.

3) They do not need to be taken with water.

4) In contact with the saliva they disintegrate immediately forming aneasy-to-swallow suspension.

5) They offer the possibility of pre-gastric absorption (mouth, pharynx,oesophagus) partially or completely avoiding the first hepatic step andimproving the bioavailability of the active ingredient.

6) They improve adherence to the treatment.

The preparation of this type of oral disintegration tablets is morecomplex than the preparation of the traditional oral tablets because ofthe significant number of technical problems that must be resolved. Thisis revealed by the numerous technologies patented or mentioned in thetechnical bibliography. So, for example, Amit Kumar et al., J. Pharm.Educ. Res., Vol. 2, Issue No 1, June 2011; Fernandez Tabares D. F. etal., Ars. Pharm., 2009, Vol. 50 No. 3, 153-167; and others.

Another alternative has been the preparation of compositions in the formof powder for suspension or small size capsules. Both are feasible onlywhen the nature of the active ingredient allows it.

Another objective of increasing technological interest, mainly duringthe last two decades has been, and is, to improve the bioavailability ofthe active ingredient.

An interesting alternative that helps to improve drug bioavailabilityare the multi-particle pharmaceutical formats (Multiple Unit Dose) whichunlike the traditional pharmaceutical forms (or Single Unit Dose) aremade up of a significant number of small particles (granules, pellets)containing the pharmaceutically active ingredient.

The multi-particle pharmaceutical compositions are presented as tabletsor capsules and they are characterised by releasing after intake asignificant number of particles that are distributed uniformly over thegastrointestinal tract. They have the advantage over traditional formsof avoiding the concentration of the whole drug contained in thecomposition, simultaneously in one part of the gastrointestinal tract,minimising the risk of local toxicity.

Generally multi-particle compositions have the following advantages:

1) More uniform distribution of the active ingredient they containthrough the gastrointestinal tract.

2) Eating has less of an effect on the absorption of the activeingredient

3) The release of the active ingredient in the composition can berepeated.

4) Statistically there is less variability of absorption betweenpatients or in the same patient with different administering.

5) Vis-à-vis active ingredients with low solubility they offer thepossibility of greater absorption linked to a better distribution of theactive ingredient in the gastrointestinal tract.

6) Greater probability of a total release of the active ingredient inthe pharmaceutical composition and consequently, greater absorption andbioavailability.

The technical literature is extensive in describing the advantages ofthe multi-particle systems over the mono-particle or single unit dose.

Also the EMEA (The European Medicines Agency—London, Jul. 29,1999—Regulation CPMP/QWP/604/96) has generally declared itself in favourof multi-particle compositions:

“The development of single non-disintegrating dosage forms isdiscouraged since their residence time in the stomach is unpredictableand in general longer than disintegrating dosage forms with multipleunits or pellets.”

Solid multi-particle pharmaceutical preparations are mentionedfrequently in the technical literature. Thus, for example:

U.S. Pat. No. 5,464,632 describes a multi-particle tablet with asuitable disintegration speed in contact with the saliva in the buccalcavity.

Document GB A 2.147.501 mentions an oral disintegration tablet thatcontains paracetamol in the presence of hydroxypropyl cellulose andethyl cellulose.

U.S. Pat. No. 5,026,560 mentions spherical particles that have a corecoated with the active ingredient and hydroxypropyl cellulose, but thetablets do not disintegrate orally.

Document JP-A-5-271054 describes the preparation of tablets thatdissolve rapidly and comprise sugars as well as the active ingredient.

However, in the previous documents aimed at oral disintegration tablets,none of the parts describe the presence of an active ingredient that isunstable vis-à-vis the acidity in the stomach and consequently, neitherdo they teach how to technically resolve the preparation ofmulti-particle pharmaceutical compositions containing drugs that areunstable in an acid medium.

Among the active ingredients sensitive to the gastric acid mediumbecause of their distinctive instability, proton pump inhibitors arefocused, like omeprazole, lanzoprazole, pantoprazole, esomeprazole orrabeprazole. All of them are very unstable vis-à-vis stomach acid pH.Almost in a few minutes they are completely destroyed. Also, suchinhibitors are used according to the patient's need in compositionscomprising between 10 and 80 milligrams per unit dose.

The instability in an acid medium and the wide dose range mentionedabove determine the need to have a flexible technology for preparing thechosen multi-particle pharmaceutical composition.

U.S. Pat. No. 7,431,942 (7 Oct. 2008) and ES 2.274.625 T3 (16 May 2007)specifically describe an oral disintegration table made up of:

1) Fine granules with an average particle diameter of 400 microns.

2) The granules are made up of a neutral core containing crystallinecellulose (40 to 50% by weight) and 50% or more lactose.

3) The cellulose and lactose cores are coated with a benzimidazolecompound (specifically, lanzoprazole) which is sensitive to the acids inthe gastric medium. Specifically, lanzoprazole, which is insoluble inwater, is added in a solid state, forming an aqueous suspension over thecellulose and lactose cores.

4) These cores are coated with a basic inorganic salt.

-   -   The basic inorganic salt described in all the examples is        magnesium carbonate in a crystalline physical state.    -   The inorganic salt is present in more than 30% of the weight of        the active benzimidazole compound to contribute to the stability        of the benzimidazole compound in an acid medium.

5) The cores subsequently comprise a first stage of aqueous entericcoating (methacrylate copolymer) and a subsequent layer made up of asugar alcohol (erythritol or mannitol).

The presence of lactose in the cores mentioned is significant,approximately 50% of the weight thereof.

In association with lactose the literature indicates that, it is notadvisable to administer it to patients who have “lactose intolerance”, acomplex pathology caused by the reduction or absence of the lactoseenzyme in the intestinal microvilli. This absence or reduction oflactose determines the impossibility of metabolising lactose and causingamong other things: poor absorption, weight loss, undernourishment orabdominal cramps.

The authors also describe other basic inorganic salts of sodium,potassium or calcium with a particularly preferable content ofapproximately 20 to 50% by weight with respect to the benzimidazolecompound contained by the pellets or particles.

The neutral core coating mentioned above is carried out by spraying witha liquid that contains the benzimidazole compound, the basic inorganicsalt and hydroxypropyl cellulose in water; organic solvent or a mixtureof organic solvent and water is not used.

The oral disintegration tablets prepared with the previous cores andknown excipients of pharmaceutical use have a disintegration time of oneminute or less.

Also European Patent Application EP 1.813.275 A1 describes thepreparation of buccal disintegration tablets.

These oral disintegration tablets comprise one or more particles orsub-tablets with enteric coating that contain the acid-sensitive drugand which comprise:

1) The neutral core made up specifically of sucrose, as table sugar iscalled technically, which is usually contraindicated in patients withdiabetes.

-   -   It does not contain an alkaline stabilising agent and it is        coated directly with a benzimidazole type drug (lanzoprazole)        which is acid-sensitive.

2) A first coating that is applied also without an alkaline stabiliser.

3) Subsequently, an inorganic type alkaline stabiliser is applied.

-   -   The alkaline stabiliser is inorganic and comprises calcium or        magnesium carbonate or a mixture of both.    -   The magnesium carbonate content is more than 50% of the contents        by weight of lanzoprazole contained in the enteric-coated        particles (so, for example, Table I indicates: lanzoprazole 30        mg and magnesium carbonate 15 mg).

4) Over the alkaline protection an enteric coating of methacrylic acidcopolymer is applied.

5) And by mixing the particles or sub-tablets with an enteric coatingcontaining one or more excipients the oral disintegration tablets areobtained.

6) Finally, according to Table 2 (page 9 of patent EP 1 813 275 A1) thetablets are prepared with 50% by weight of two optionally chosenexcipients that contain lactose, they are:

a) STARLAC (made up of 85% of lactose monohydrate and 15% cornstarch)

-   -   Specifically tablets of 708 mg contain 378.5 mg of STARLAC,        others of 750 mg contain 394 mg and tablets of 592 mg contain        322 mg of STARLAC, virtually, about 300 mg of lactose per        tablet.

b) CELLACTOSE 80 (made up of 75% monohydrate lactose and 25% cellulose)

-   -   Specifically, tablets with an end weight of 526 mg, have 234 mg        of CELLACTOSE 80 and tablets with an end weight of 560 mg        contain 249 mg of CELLACTOSE 80, also with a high lactose        content.    -   Administering tablets with a high lactose content is not        advisable for patients who need lanzoprazole, but who        specifically have “lactose intolerance” because of the known        problems caused in these patients when they take lactose because        of the absence of the lactose enzyme in the intestinal villi.

Both patents describe respectively:

a) The use of lactose and cellulose cores in different percentagespreparing tablets with a high lactose content

b) The use of sugar or sucrose cores.

c) They suffer from the drawback that the intake of lactose iscontraindicated in patients with “lactose intolerance” and the intake ofsugar is contraindicated in patients with diabetes.

d) Both limit themselves to using an inorganic alkaline stabilisingagent, in solid state and with a high content. This contributes to thelarger average size of the pellets they make.

However, neither of the documents contain the teachings or unexpectedtechnical advantages of using pure cellulose cores, as described in thisinvention.

Therefore there is still the need to provide small size tablets thatcontain active ingredients which are labile in the acid medium in thestomach, and with sufficient stability to release the active ingredientearly in the intestinal pH where the ingredient is absorbed, and whichallow the preparation of multi-particle pharmaceutical compositions thatare easy to take irrespective of whether they are in the form of oraldisintegration tablets, powder for suspension or capsules, and which canbe administered also to patients with diabetes or with lactoseintolerance.

SUMMARY OF THE INVENTION

Therefore a first object of the invention is to provide pellets thatcomprise a proton pump inhibitor with convenient stability in thegastric acid medium for preparing multi-particle pharmaceuticalcompositions for oral use.

Another object of the invention is to provide new pure cellulose pelletsthat contain the active ingredient with benzoimidazole structure andwith inhibiting activity on the proton pump that are useful forpreparing a pharmaceutical composition which, after intake, do notdegrade at pH 4.5 for 45 minutes and have the capacity to release saidinhibitor at pH 6.8.

Another object of the invention is to provide new pure cellulose pelletsthat contain the active ingredient with benzoimidazole structuredistributed over the cellulose cores.

Another object of the invention is to provide small size enteric-coatedpellets of a proton pump inhibitor allowing the preparation of oraldisintegration multi-particle pharmaceutical compositions, powder forsuspension or capsules smaller than those commercially available.

Another object of the invention is to provide enteric-coated pelletsthat comprise a proton pump inhibitor with sufficient technologicalflexibility for them to be applied to the preparation of differentpharmaceutical compositions that are needed in each case and whichaccording to the characteristics of the pellets in a different averagediameter range, withstand the compression stage during the preparationof the multi-particle pharmaceutical compositions in the form of oraldisintegration tablets with the characteristic advantages thereof.

Another object of the invention is to provide small size enteric-coatedpellets but which comprise a proton pump inhibitor and have a highcontent thereof thereby ensuring the necessary intake for the patient'streatment.

Another object of the invention is to provide pharmaceuticalcompositions that are presented in the multi-particle form with thebiopharmaceutical advantages broadly described for these compositions,and with the ability to facilitate their intake by the patient andspread the dosage.

Another object of this invention is to provide pharmaceuticalcompositions that are presented in the multi-particle form, which can beadministered to patients with both diabetes and lactose intolerance.

DETAILED DESCRIPTION OF THE INVENTION

This invention relates to a new procedure for preparing particles orpellets comprising pure cellulose cores containing on the surfacethereof an even distribution of a proton pump inhibitor withbenzimidazole structure together with a dibasic amino acid as theinternal protection agent mainly in amorphous form, preferablycompletely amorphous, a recrystallisation inhibitor of the dibasic aminoacid (preferably polyvinylpyrrolidone and very preferablypolyvinylpyrrolidone K 30) and an enteric coating as the externalcoating agent which together determine the chemical stability of theactive ingredient vis-à-vis the acid medium in the stomach in the chosenpharmaceutical composition containing said pellets.

The pure cellulose cores have the advantage of being inert, thecellulose is not hydrolysed in the body and it is not contraindicated inpatients with diabetes or with “glucose intolerance”.

The cellulose is formed by the union of beta-1,4 glucopyranose moleculesthat form beta-1,4 glucosidic bonds which when hydrolysed produceglucose. But, in human beings and animals due to the lack of thecellulase enzyme they do not produce glucose; consequently the purecellulose cores are inert.

The literature also highlights that it is important to include cellulosein the human diet as a dietary fibre to facilitate digestion.

The previous art does not describe the coating of pure cellulose coreswith a hydroalcoholic suspension that contains previously dissolved, aproton pump inhibitor with benzimidazole structure and a dibasic aminoacid in a mixture of ethanol and water (preferably between 80:20 and95:5) which subsequently is transformed into a suspension when talcum isadded together with the cohesion or binding agent (polyvinylpyrrolidone)which acts by inhibiting the recrystallization of the dibasic aminoacid.

The new above solution of the proton pump inhibitor with benzimidazolestructure in ethanol-water (preferably between 80:20 and 95:5)determines the even distribution of the proton pump inhibitor withbenzimidazole structure over all the pure cellulose cores, with saidprevious dissolution preventing the greater concentration of the protonpump inhibitor with benzimidazole structure over part of the total massand ensures an uniform distribution of all the particles.

Neither do the state of the art documents describe the new use oforganic agents as alkaline stabilisers (dibasic amino acids) withadvantages not described under the inorganic stabilisers mentioned inthe literature.

The dibasic amino acid used as the internal protector in this inventionis dissolved previously together with the proton pump inhibitor and,this way, through subsequent elimination of the solvent containing them,an even distribution of the dibasic amino acid and the active ingredientis obtained over the surface of the cores, with both components (dibasicamino acids and active ingredient) moving into a solid state.Unexpectedly, this way sufficient internal protection is offered to theactive ingredient unstable in the acid medium.

The notable protection of the dibasic amino acid is effective with onlyabout 10.0% by weight with respect to the weight of the activeingredient. This advantage is not described previously in the technicalliterature.

Whereas, with the inorganic agents mentioned in the previous art, whichare in the solid state, a simple physical mixture is formed with theproton pump inhibitor agent and therefore it is necessary to use a highpercentage (30 to 50%) of said inorganic agents to ensure the stabilityof the proton pump inhibitor agent.

These new characteristics, together with the small average size of theenteric-coated pellets (smaller than 710 microns and preferably smallerthan 500 microns) and the stability in the acid medium of the activeingredient they contain, enable them to transform subsequently into newchosen pharmaceutical compositions.

This invention provides a new procedure for preparing pellets withsufficient technological flexibility to apply them to the preparation ofdifferent pharmaceutical compositions that are needed in each case andaccording to their characteristics as pellets in a different averagediameter range.

The chosen oral compositions are presented in the form of oraldisintegration tablets (ODT), powder for suspension in water or otherliquids, capsules (preferably smaller than those commercially available)or multi-particle tablets.

They all contribute to the easy intake by patients and havemulti-particle properties.

They contain the proton pump inhibitor with benzoimidazole structure andexcellent protection against the acid pH in the stomach and it ispossible to obtain them as described in this invention in theexperimental part, using dibasic amino acids in mainly amorphous stateand pure cellulose cores.

The active ingredient with benzoimidazole structure and proton pumpinhibitor activity contained in the pharmaceutical composition in theform of new pure cellulose pellets, after intake, does not degrade at pH4.5 for 45 minutes and has the capacity to release said inhibitor at pH6.8 in no more than 45 minutes according to the assay described inBritish Pharmacopea (BP) 2012 Vol. III.

-   -   The instability of omeprazole in the acid medium is widely known        and described in the technical literature and in the literature        on patents.    -   It is also known that a simple enteric coating using some of the        usual procedures described in the technical literature for other        active ingredients, is not sufficient for preparing omeprazole        pharmaceutical compositions with convenient stability in the        gastric acid medium.    -   A practical problem that this invention has resolved and which        is also applicable to other proton pump inhibitors with        benzimidazole structure like esomeprazole, lanzoprazole,        pantoprazole or rabeprazole.

The compositions of this invention are presented in the multi-particleform with the biopharmaceutical advantages broadly described for thesecompositions, with the capacity to facilitate intake thereof by thepatient and spread the dose.

-   -   The chosen composition of this invention is presented preferably        in the form of oral disintegration tablets (ODT).    -   The oral disintegration tablets (ODT) can be administered        directly. But, they have the characteristic of being able to be        poured over water or another drink and after their complete        disintegration, which takes less than a minute and preferably        less than 30 seconds, they can be administered as a suspension        to adult patients with swallowing problems or paediatric        patients also. In both cases, according to the volume of        suspension administered, it is possible to regulate the dose.        The ODT tablets described also offer convenient dose        flexibility.    -   The small size of the enteric-coated pellets containing the        proton pump inhibitor with benzimidazole structure in this        invention and the possibility of selection through sieving        during the preparation thereof also enable preparing capsules        smaller than those commercially available. The commercially        available pellets containing the proton pump inhibitor with        benzimidazole structure or those described in the literature        have an average particle size range of about 1000 microns. A        size significantly larger than those in this invention.        Consequently, the capsules containing them are a larger size.    -   The small capsules described in the examples in the experimental        part maintain the multi-particle nature and facilitate intake        thereof by patients with swallowing problems. They have the        following practical applications:

a) due to being smaller than other capsules they contribute toadministering to patients with swallowing problems (even when they haveno problems with normal eating).

b) it is possible to pour the contents of the capsule into water oranother liquid and administer the suspension gradually in spoonfuls.

c) in hospitalised patients who have a nasogastric tube in place, viathis route it is possible to administer a suspension made up of thesmall pellets from the capsules and water.

The preparation of enteric-coated pellets containing the proton pumpinhibitor with benzimidazole structure according to this invention iscarried out over neutral pure cellulose cores.

-   -   The pure cellulose cores as mentioned, have the advantage of        being inert, since the cellulose does not hydrolyse in the        intestine because of the lack of the cellulase enzyme and it        does not produce glucose in human beings. Consequently they can        be applied to patients with diabetes and also it is known that        in the human diet the presence of cellulose in the intestine        facilitates digestion.    -   To date no description has been given of the use of neutral pure        cellulose cores for preparing pellets coated with proton pump        inhibitors.    -   Neither has a description been given of the use of such pellets        in a new association of the proton pump inhibitor with        benzimidazole structure and a protective agent of the dibasic        amino acid type. As will be explained, and particularly useful        and necessary for preparing a composition that is stable in an        acid medium.    -   A description has only been given, as mentioned in the        background to the invention, of: A) cores made up of cellulose        and lactose, and B) others made up of sugar both used as a        support for lanzoprazole, and not suitable for applying to        patients with “lactose intolerance” or diabetes.

Commercially pure cellulose cores exist with a broad particle sizerange. These include: cores with a particle size range between 106 and212 microns, between 150 and 300 microns, between 300 and 500 microns,between 500 and 710 microns and others of a larger size. Some are soldunder the Celphere Brand and they are prepared by the Company AsahiKasei.

These pure cellulose cores, as will be seen, are of special practicalinterest for the present invention to allow for the preparation ofpellets with a different average diameter range and, what is veryimportant, with a high active ingredient content. Both aspects areparticularly interesting for preparing the chosen pharmaceuticalcomposition.

Using an organic internal protection agent of the dibasic amino acidtype during the preparation of the pellets, surprisingly allows an evencoating of the proton pump inhibitor with benzimidazole structure overthe cellulose cores. In principle the internal protection agent isdissolved in the medium and finally, together with a binding agent thatinhibits the recrystallisation of the amino acid when the solvent isremoved, the amino acid is deposited over the particles mainly (and evencompletely) in an amorphous physical state.

-   -   The intimate or internal protection agent of the proton pump        inhibitor with benzimidazole structure is a dibasic amino acid,        preferably selected from among lysine, histidine or 1-arginine,        with 1-arginine being the most preferred one.    -   The prior dissolution of the internal protection agent of the        dibasic amino acid in water and of the proton pump inhibitor        with benzimidazole structure in the water-ethanol mixture in the        presence of the binding agent (polyvinylpyrrolidone) determines        that the internal protection agent is mainly (or even        completely) in an amorphous state when the solvent is eliminated        and it is distributed evenly together with the proton pump        inhibitor with benzimidazole structure over the cellulose cores,        ensuring intimate or internal protection vis-à-vis acids and        humidity.

Surprisingly, the practical importance of the previous dissolution ofthe dibasic amino acid in the presence of the binding agent(polyvinylpyrrolidone) was observed under a microscope and it is theobject of special practical interest for this invention. Thepolyvinylpyrrolidone known as a binding agent acts simultaneously as acrystallisation inhibitor during the evaporation over the cellulosecores of the solvents mixture (water-ethanol) and determines:

a) Even distribution of the dibasic amino acid and of the proton pumpinhibitor with benzimidazole structure over the surface of the purecellulose cores.

b) Presence of the dibasic amino acid in an amorphous state.

c) In the physical amorphous state, the dibasic amino acid offers agreater contact surface with the acid medium, and consequently, it hasan unexpected neutralising capacity

d) Only the presence of about 10% of the dibasic amino acid by weight isnecessary with respect to the weight of the proton pump inhibitor withbenzimidazole structure (on the surface of the pure cellulose cores) toensure protection of the active ingredient from the acidity.

-   -   The contents of only about 10% of the dibasic organic agent        constitutes a significant difference with the basic protective        but inorganic agents that exist in a physical crystalline state        and which are mentioned and described previously in the        background art.    -   The basic inorganic agents must exist in high contents to ensure        the stability in the acid medium of the active ingredient.    -   Thus it is mentioned, for example, in US patent 7.431.942 where        the magnesium carbonate exists as between 20 and 40% of the        weight of the benzimidazole compound and in EP 1.813.275 where        the contents is more than 50%.    -   The smaller necessary content using a dibasic amino acid also        determines the small size of the pellets obtained, and allows        for the preparation of the different chosen pharmaceutical        compositions of this invention.

Surprisingly, it has been observed experimentally that the binding agent(polyvinylpyrrolidone) prevents the recrystallisation of the dibasicamino acid, preferably lysine, histidine or 1-arginine, and verypreferably 1-arginine, dissolved in a mixture made up of water-ethanol(between 20:80 and 5:95) after the evaporation of the solvent, and itdetermines the even distribution of the dibasic amino acid and theactive ingredient over all the particles.

The drying of the pellets to humidity lower than 1%, surprisingly showedthat it is particularly useful, since with time it determines thegreater stability of the proton pump inhibitor with benzimidazolestructure they contain, in the acid medium and vis-à-vis humidity.

Surprisingly it has been achieved that the pellets obtained by theprocedure described in the examples have a high content of proton pumpinhibitor with benzimidazole, more than 10.5%, preferably more than12.0%.

The high content of the proton pump inhibitor with benzimidazolestructure in the pellets prepared with the procedure described allowsfor the preparation of multi-particle pharmaceutical compositions, thatare easy to take and surprisingly useful for patients with swallowingdifficulties.

The procedure for preparing the enteric particles that contain theproton pump inhibitor with benzimidazole structure, which is the objectof this invention, includes four continuous stages. Each stage fulfils aspecific function and the whole determines the stability in the acidmedium that the multi-particle pharmaceutical composition needs.

Preferably, the procedure, as illustrated in the preparation examples,comprises diagrammatically:

-   -   Stage I: The object is to provide pure cellulose cores coated        evenly with the proton pump inhibitor, a dibasic amino acid, as        protection agent, previously dissolved in an alcoholic solution,        to finally end up in an amorphous state (or, at least, mainly        amorphous), the agent inhibiting the recrystallisation of the        internal protection and talcum.    -   The pure cellulose particles chosen for this invention have        preferably an average diameter range between 150 and 300        microns. For example: Celphere type CP-203 or the like.    -   According to the chosen pharmaceutical composition other pure        cellulose cores are also useful with different average particle        diameter ranges than the one above (for example: 106 to 212        microns, Celphere type CP-102), 300 to 500 microns (Celphere        CP-305).

The incorporated talcum has preferably a particle size average diameterof about 74 microns (#200 mesh).

-   -   Once prepared and dried the cellulose cores with the proton pump        inhibitor in the benzimidazole structure in the indicated form        contain:

1) The dibasic amino acid in amorphous form uniformly distributedtogether with the proton pump inhibitor with the benzimidazole structureover the cellulose cores, produces internal protection to the acidmedium, and

2) Talcum, which due to its capacity to absorb humidity also contributesto the stability of the proton pump inhibitor.

-   -   Stage II: The object is to isolate through spray coating the        particles obtained in Stage I.

Isolation that is carried out preferably with hydroxypropylmethylcellulose previously suspended in isopropyl alcohol-water,together with other components (polyethylene glycol 400, polysorbate 80and titanium dioxide) as will be specified in the Examples.

The hydroxypropyl methylcellulose and other components intended toisolate the pure cellulose cores coated according to Stage I) and asdescribed in the corresponding examples, can be replaced withcommercially available mixtures that fulfil the same function, i.e.: actas isolating agents. So, for example, it is possible to use thecommercial composition called Opadry White YS-1-7003 (hydroxypropylmethylcellulose, polyethylene glycol, polysorbate 80 and titaniumdioxide).

-   -   Stage III: This corresponds to the enteric coating of the        particles obtained in Stage II.

Surprisingly, it has been observed that the particles obtained in StageII accept subsequently and indifferently an enteric coating using twodifferent methods: a) hydroalcoholic and b) aqueous. In both cases suchcoating fulfils its specific function as described in the experimentalpart.

The two preferred coatings are:

-   -   Enteric coating in hydroalcoholic medium.    -   The external protection agent is made up of Type A copolymer        (USP/NF), triethyl citrate, glyceryl monostearate, polysorbate        80 and titanium dioxide and ethyl acrylate and        methylmethacrylate copolymer dispersion (USP/NF).    -   In a non-limiting way a commercially available Type A copolymer        is Eudragit L 100 and an ethyl acrylate and methylmethacrylate        copolymer (USP/NF) is Eudragit NE 30 D.    -   Enteric coating in aqueous medium.

Optionally, the external protection of the particles obtained in StageII was also carried out in an exclusively aqueous medium containingmethacrylic acid copolymer, triethyl citrate, glyceryl monostearate andpolysorbate 80 as illustrated in the experimental part.

In this case also surprising was the high content of the proton pumpinhibitor with benzimidazole structure in the enteric-coated pelletsobtained, reaching 23%.

Such content has not been mentioned regarding enteric-coated pelletscontaining the proton pump inhibitor with the benzimidazole structure inthe scope of the commercial supply of pellets containing the proton pumpinhibitor with benzimidazole structure.

Neither in the technical literature to date are pellets with such a highcontent described.

The high content of the pellets obtained facilitates the subsequentpreparation of the chosen pharmaceutical composition.

-   -   Stage IV: The object was to dry to humidity lower than 1% the        pellets or particles obtained in Stage III and, preferably,        select the particles by size range.    -   The dried enteric particles obtained in Stage III were sieved        and the fraction of particles with an average size lower than        590 microns was selected for preparing the pharmaceutical        composition.

Unexpectedly it was observed that the pellets with humidity more than 1%lost their initial stability to the acid medium and temperature morequickly.

Preferably, the coating suspension in Stage I) for coating the cellulosecores was prepared by:

i) dissolving the dibasic amino acid in water;

ii) adding ethanol to the previous solution (i) up to an ethanol-waterproportion between 80:20 and 95:5 and preferably 90-10; and the protonpump inhibitor up to the complete dissolution thereof;

iii) adding talcum to the solution obtained in ii) to form a suspension,and subsequently adding polyvinylpyrrolidone (preferablypolyvinylpyrrolidone K30) under stirring, preferably between 8500 and10500 r.p.m, and very preferably at 9500 r.p.m.;

iv) filtering the suspension obtained in iii), preferably through a 250micron mesh maintaining the suspension under stirring;

v) applying the previous suspension (iv) over pure cellulose cores,preferably with an average diameter of 150 to 300 microns,advantageously using a Wurster system (also called bottom spray), andpreferably maintaining the temperature at 38 to 42° C. throughout theprocess; and

vi) preferably sieving with a 500 micron mesh, to eliminate large sizeagglomerates.

The new enteric-coated pellets obtained according to the previousprocedure and described in the experimental part have revealed:

a) That they have excellent stability vis-à-vis the proton pumpinhibitor they contain in a pH 4.5 medium during 45 minutes and thecapacity to release said inhibitor at pH 6.8 in no more than 45 minutesaccording to an assay described in British Pharmacopea 2012 Vol. III, aswill be seen in the Experimental Part.

b) High content of proton pump inhibitor with benzimidazole structure inthe enteric particles, not described previously, which is more than10.5% and even more than 12.0%, according to the level of entericcoating (Stage II) chosen. With a content over 14% being especiallypreferable for the pharmaceutical composition.

c) That the procedure described is new because of the neutral purecellulose cores and because of the presence of the organic internalprotector (dibasic amino acid).

d) That the amino acid is present in an amount preferably less than orequal to 10% by weight with respect to the weight of the existent protonpump inhibitor with benzimidazole structure.

e) That it is applicable to neutral cores with different particle sizeranges than the one mentioned above.

f) That the procedure offers the necessary and sufficient flexibility toprepare, according to the average diameter of the particles obtained ineach case, the chosen multi-particle pharmaceutical composition.

This invention allows the chosen pharmaceutical composition preparedwith the enteric particles to be presented (as described in thecorresponding examples in the Experimental Part) indistinctively in thefollowing formats:

a) Oral disintegration tablets.

b) Powder for suspension.

c) Capsules in a smaller size with an equal content of the activeingredient as other commercially available capsules to date, and whichfacilitate the intake thereof.

d) And in associations with microcapsules of sodium diclofenac preparedpreviously as described, inter alia, in international patent applicationWO 2013/139377 in the name of the same applicant of this invention.Preferably the prepared associations contain 25 to 100 mg ofmicroencapsulated and enteric sodium diclofenac and between 10 and 40 mgof proton pump inhibitor with benzimidazole structure in pellets, andthey are presented as oral disintegration tablets, powder for suspensionor capsules.

In all cases new multi-particle and small size compositions can beprepared thanks to the fact that the pellets included have a highconcentration of active ingredient.

In a non-limiting way, this invention will be described in greaterdetail in the following examples that describe the way of carrying itout practically.

EXPERIMENTAL PART Example I—Preparation of Enteric-Coated PelletsContaining Omeprazole

Starting with pure cellulose (100%) neutral cores and omeprazole pureactive ingredient, with successive stages of bottom spray coating, usinghydroalcoholic suspensions, enteric-coated omeprazole pellets wereobtained, sized between 420 and 590 μm.

The preparation was carried out in four independent stages with each onefulfilling specific functions. They were:

Stage I: Coating pure cellulose cores with a hydroalcoholic solutionthat contains dissolved omeprazole and a dibasic amino acid, and formsthe suspension by incorporating talcum and subsequently the agentpolyvinylpyrrolidone.

The suspension presented the composition mentioned in Table 1.

TABLE 1 Raw Material Grams/100 g of suspension Omeprazole 14.7Polyvinylpyrrolidone K-30 3.6 L-arginine 1.5 Talcum 1.5 Ethanol 70.8Water 7.9

The suspension was prepared by dissolving the 1-arginine in water;adding ethanol and dissolving omeprazole in the ethanol-water mixtureformed. By adding the talcum it was transformed into a suspension thatwas homogeneised under stirring for 20 minutes. Subsequently, thepolyvinylpyrrolidone K-30 was added, it was homogenised under stirringfor another 20 minutes and the suspension was filtered through a 250microns mesh.

Using bottom spray, a total of 15372 grams of this suspension, wereapplied to 2500 grams of pure cellulose cores sized between 150 and 300μm, maintaining the temperature of the product between 38 and 42° C.throughout the process. At the end of this stage, a 500 μm sieve wasused to eliminate agglomerates that could have formed during theprocess. Finally obtaining 5250 grams of omeprazole pellets protected bythe dibasic amino acid.

Stage II: Isolating the particles obtained in Stage I

A hydroalcoholic suspension was prepared with hydroxypropylmethylcellulose (HPMC) and other components indicated in the formula inTable 2, under stirring for one hour.

TABLE 2 Composition of the isolating coating suspension. Raw MaterialGrams/100 g of suspension Hydroxypropyl methylcellulose (6 cp) 3.66Hydroxypropyl methylcellulose (3 cp) 3.66 Polyethylene glycol 400 0.96Polysorbate 80 0.12 Titanium Dioxide 3.6 Isopropyl Alcohol 71 Water 17

A total of 2625 grams of the cores coated in Stage I were added to fluidbed equipment heated previously to 40° C. and they were coated usingbottom spray with 7066 grams of the isolating suspension above.Throughout the process the temperature was maintained at 40 to 45° C.Using a 590 μm sieve agglomerates from the process were eliminated,finally obtaining 3350 grams of omeprazole pellets, protected by thedibasic amino acid and isolated with a hydroxypropyl methylcellulosecoating.

The mixture of excipients made up of hydroxypropyl methylcellulose,polyethylene glycol, polysorbate 80 and titanium dioxide can bereplaced, for example, with Opadry

White Ys-1-7003 or the like.

Stage III: Hydroalcoholic enteric coating of the particles obtained inStage II.

A hydroalcoholic preparation was prepared with A type methacrylic acidcopolymer (USP/NF) according to the formula in Table 3 below:

TABLE 3 Composition of the enteric coating suspension. Raw MaterialGrams/100 g of suspension Ethyl acrylate and methylmethacrylate 7.94copolymer Triethyl citrate 1.59 Titanium Dioxide 1.00 Isopropyl Alcohol84.60 Water 4.87

In the fluid bed a total of 2500 grams of the particles obtained inStage II were added, after heating the equipment to 35° C., and theywere coated with 28775 grams of the above suspension maintaining thetemperature between 32 and 38° C. throughout the process. Using a 710 μmmesh agglomerates that could have formed during the process werediscarded, finally obtaining omeprazole pellets, protected by thedibasic amino acid, isolated with a coating of hydroxypropylmethylcellulose and gastro-resistant components.

The product revealed good analytical results in a pH 4.5 medium for 45minutes and the capacity to release said inhibitor at pH 6.8 in no morethan 45 minutes according to the assay described in BP 2012 Vol. III.

Stage IV: Drying the particles with internal and external protectionobtained in Stage III and size selection.

The particles obtained in Stage III were dried to a humidity level lowerthan 1% in the same fluid bed equipment. The temperature of the productwas maintained at 40° C. throughout the said drying.

Previously and using several samples dried to a different percentage ofresidual humidity, on an experimental basis it was observed that ahumidity content more than 1.0% favoured the breakdown of the omeprazolecontent in the pellets obtained and simultaneously determined theincrease in related substances (or substances originating from thebreakdown of omeprazole).

Using a sieving tower (Zonytest) the particles between 420 and 590microns were selected.

The particles sized more than 590 microns were eliminated (approximately1.5%).

Analytically, it revealed:

1) That the omeprazole content per unit of weight of the pelletsobtained was 12.6% and their relative humidity was less than 1%.

2) That the pellets obtained fulfilled the gastro-resistant anddissolution assays described in BP.

3) It showed that in Stage II effective isolation was obtained with aweight gain expressed in hydroxypropyl methylcellulose more than 19%.

4) That the particles fulfilled the assays on related substancesdescribed in BP 2012 Vol. III.

5) Accelerated thermal stress assay:

-   -   It was shown that the omeprazole pellets obtained and preserved        at 60° C. for 10 days did not have a significant reduction of        the active ingredient concentration (only 0.70%) and little        increase in the value found in related substances (0.50%).    -   In equal conditions, commercially available pellets with a        larger average particle size range used a references presented a        reduction in the omeprazole content of about 2.3% and an        increase in the related substances of about 3.2%, confirming the        advantages of the procedure described.    -   As the ethyl acrylate and methylmethacrylate copolymer, in a        non-limiting manner, it is possible to use: Eudragit L 100.

The procedure described was also applied to esomeprazole.

Example II—Preparing Enteric-Coated Pellets that Contain Omeprazole witha Larger Plasticiser Content and Talcum

The preparation was carried out in four independent stages that eachfulfil specific functions.

Stage I was similar to that described in Example I, but in this case atotal of 2000 grams of pure cellulose cores were used and they werecoated with 17837 grams of suspension.

Stage II was similar to that described in Example I. With these twostages microparticles of omeprazole were obtained, protected by thedibasic amino acid and isolated with a hydroxypropyl methylcellulosecoating. Subsequently with the protected and isolated microparticlesenteric-coated pellets were obtained with a greater concentration ofplasticiser (triethyl citrate) and talcum to that used in Example Iaccording to the description.

Stage III: Hydroalcoholic enteric coating of the particles obtained inStage II.

A hydroalcoholic preparation was prepared with A type methacrylic acidcopolymer (USP/NF) according to the following formula:

Raw Material Grams/100 g of suspension Methacrylic acid copolymer 7.94Triethyl citrate 2.38 Titanium Dioxide 1.00 Talcum 1.00 IsopropylAlcohol 83.28 Water 4.40

A total of 1300 grams of the particles obtained in Stage II were addedto a fluid bed equipment, previously heated to 35° C., and they werecoated with 13930 grams of the suspension above maintaining thetemperature between 30 and 35° C. throughout the whole process. Using a710 μm sieve agglomerates formed in the process were discarded, finallyobtaining omeprazole pellets, protected by the dibasic amino acid,isolated with a coating of hydroxypropyl methylcellulose andgastro-resistant components.

The product revealed appropriate stability in the pH 4.5 medium for 45minutes and the capacity to release said inhibitor at pH 6.8 in no morethan 45 minutes according to the assay described in BP 2012 Vol. III.

Stage IV: Drying the particles with internal and external protectionobtained in Stage III and size selection.

The particles obtained in Stage III were dried to a humidity level lowerthan 1% in the same fluid bed equipment. The temperature of the productwas maintained at 40° C. throughout the drying.

Using the sieving tower (Zonytest) the particle size distribution wasdetermined. It was observed that 97% of the particles had a size between420 and 590 microns. The particles with a size over 590 microns wereeliminated (approximately 1.5%).

Analytically: The behaviour of the pellets obtained by increasing theplasticiser content to 30% was similar to the pellets obtained accordingto Example I above with respect to: humidity (lower than 1%) andgastro-resistancy, dissolution and related substances assays. Theomeprazole content was 15.0%.

The larger content of triethyl citrate during Stage III determined amore flexible coating resistant to the compression strength during thepreparation of oral dispersion tablets according to the generalprocedure described in subsequent examples.

Example III—Preparation of Enteric-Coated Pellets Containing Omeprazoleand Pure Cellulose Core with Average Diameter Between 300 and 500Microns

Starting with pure cellulose (100%) neutral cores, sized between 500 and300 μm and pure omeprazole active ingredient, using successive stages ofbottom spray coating using hydroalcoholic suspensions, omeprazoleenteric-coated pellets were obtained, sized between 500 and 710 μm.

The preparation was carried out in four independent stages with each onefulfilling specific functions. They were:

Stage I: Coating cellulose cores with a hydroalcoholic suspensioncontaining dissolved omeprazole, and a dibasic amino acid in amorphousstate, a suspension that is formed by adding talcum to the solution ofomeprazole and amino acid and subsequently adding polyvinylpyrrolidoneas the agent inhibiting the recrystallisation of the dibasic amino acidpresent in the suspension.

As the first step, the suspension was prepared containing the protonpump inhibitor, the dibasic amino acid (1-arginine) as internalprotector dissolved in the solvent, a binding agent(polyvinylpyrrolidone K-30) and talcum, according to the formula inTable 1.

TABLE 1 Composition of the active coating suspension. Raw MaterialGrams/100 g. of suspension Omeprazole 14.7 Polyvinylpyrrolidone K-30 3.6L-arginine 1.5 Talcum 1.5 Ethanol 70.8 Water 7.9

The coating suspension was prepared by previously dissolving 1-argininein water.

Subsequently the ethanol was added, and the omeprazole was dissolved;then talcum was added forming a suspension.

The suspension was homogeneised for 20 minutes, the polyvinylpyrrolidoneK-30 was added and it was homogeneised for 20 minutes more. Finally thesuspension was filtered through a 250 μm mesh.

Using bottom spray, a total of 5704 grams of this suspension was appliedover 3000 grams of pure cellulose cores sized between 300 and 500 μm,maintaining the temperature of the product at 40° C. throughout theprocess. At the end of this stage, a 710 μm sieve was used to eliminateagglomerates that could have formed during the process. Finallyobtaining 4106 grams of omeprazole pellets protected by the dibasicamino acid.

Stage II: Isolating the particles obtained in Stage I.

A hydroalcoholic suspension was prepared with hydroxypropylmethylcellulose (HPMC) and other components indicated in the formula inTable 2, under stirring for one hour.

TABLE 2 Composition of the isolation coating suspension. Raw MaterialGrams/100 g. of suspension Hydroxypropyl methylcellulose (6 cp) 3.9Hydroxypropyl methylcellulose (3 cp) 3.9 Polyetylene glycol 400 0.96Polysorbate 80 0.12 Titanium Dioxide 3.9 Isopropyl Alcohol 70 Water 17

A total of 4000 grams of the cores coated in Stage I were added to fluidbed equipment previously heated to 40° C. and they were coated usingbottom spraying with 3335 grams of the above isolation suspension.Throughout the process the temperature was maintained at 38 to 42° C.Using a 710 μm mesh agglomerates from the process were eliminated,finally obtaining a total of 4326 grams of omeprazole pellets, protectedby the dibasic amino acid and isolated with a coating of hydroxypropylmethylcellulose.

The mixture of excipients made up of hydroxypropyl methylcellulose,polyethylene glycol, polysorbate 80 and titanium dioxide can bereplaced, for example, with Opadry White Ys-1-7003 or the like.

Stage III: Enteric hydroalcoholic coating of the particles obtained inStage II.

A hydroalcoholic suspension was prepared with A type methacrylic acidcopolymer (USP/NF), according to the formula in the following Table 3:

TABLE 3 Composition of the enteric coating suspension. Raw MaterialGrams/100 g. of suspension Methacrylic acid copolymer 7.94 Triethylcitrate 1.27 Talcum 0.79 Isopropyl Alcohol 84.86 Water 5.14

A total of 3600 grams of the particles obtained in Stage II were addedto fluid bed equipment, previously heated to 35° C., and they werecoated with 21600 grams of the above suspension maintaining thetemperature between 32 and 38° C. throughout the process. Using a 1000μm sieve agglomerates formed during the process were discarded, finallyobtaining omeprazole pellets, protected by the dibasic amino acid,isolated with a coating of hydroxypropyl methylcellulose andgastro-resistant components.

The product revealed good results in the pH 4.5 medium for 45 minutesand the capacity to release said inhibitor at pH 6.8 in no more than 45minutes according to the assay described in BP 2012 Vol. III.

Stage IV: Drying the particles with internal and external protectionobtained in Stage III and size selection.

The particles obtained in Stage III were dried to humidity lower than 1%in the same fluid bed equipment, using a temperature of 40° C.

Using a sieving tower (Zonytest) the particle size distribution wasdetermined. It was observed that 93% of the particles were sized between500 and 710 microns. The larger size particles were eliminated.

Analytically, it was revealed:

1) That the omeprazole content per unit of weight of the pelletsobtained was 10.67% and its relative humidity was lower than 1%.

2) Taking a sample prior to drying to humidity lower than said 1%, itwas shown unexpectedly that, when the humidity content is more than 1%it quickly accelerates the breakdown of the omeprazole contained in thepellets obtained. Also the presence of related substances issignificantly increased.

3) The pellets obtained fulfilled the gastro-resistancy and dissolutionassays described in British Pharmacopea.

-   -   It was shown that in Stage II effective isolation was obtained        with a weight gain expressed in hydroxypropyl methylcellulose        greater than 6%.

4) That the particles fulfilled assays on related substances describedin BP 2012 Vol. III.

5) Accelerated thermal stress assay:

-   -   The reduction in the titration value of the omeprazole pellets        with humidity lower than 1% obtained and preserved at 60° C. for        17 days was 1.32% and the increase in the related substances was        1.32%.    -   In equal conditions, in a period of just 10 days, commercially        available pellets with a greater average particle size range        used as references showed a reduction in the omeprazole content        of about 2.3% and an increase in the related substances of about        3.2%, confirming the advantages of the procedure described.    -   The difference in behaviour regarding the temperature and time        revealed the greater stability of the new pellets in comparison        with conventional pellets.

6) Accelerated stability assay:

-   -   It was shown that the omeprazole pellets obtained and preserved        at 40° C. with 75% RH, for 7 months, did not have any        significant reduction in the concentration of the active        ingredient and little increase in the value found with related        substances.

Example IV—Preparation of Enteric-Coated Pellets Containing Omeprazoleon Pure Cellulose Core and with Aqueous Enteric Coating

Enteric-coated omeprazole pellets were obtained starting with purecellulose (100%) neutral cores with an average size between 150 and 300microns, coating them with successive steps of bottom spraying.

Omeprazole microparticles previously protected by a dibasic amino acidand isolated with a hydroxypropyl methylcellulose coating were coatedwith an aqueous enteric coating, obtaining pellets sized between 350 and500 μm and with an omeprazole content over 20%.

The preparation was made in four independent stages each one fulfillingspecific functions. These were:

Stage I: Coating cellulose cores with a hydroalcoholic suspensioncontaining omeprazole and a dibasic amino acid dissolved in anethanol-water mixture (90/10) the suspension being formed by addingtalcum and to the suspension formed the agent inhibiting therecrystallisation of the dibasic amino acid (polyvinylpyrrolidone) andhomogeneisation is added

It was carried out according to Stage I of Example I with the sameformula and process conditions.

A total of 17837 grams of hydroalcoholic suspension of omeprazole wereapplied over 2000 grams of pure cellulose cores.

Stage II: Isolation of the particles obtained in Stage I.

It was carried out with the same formula, preparation and processconditions used in Stage II of Example I.

Stage III: Aqueous enteric coating of the particles obtained in StageII.

An aqueous suspension of C Type methacrylic acid copolymer (USP/NF) wasprepared according to the formula in Table 1:

TABLE 1 composition of the enteric coating suspension. Raw MaterialGrams/100 g.of suspension Methacrylic acid and ethyl methacrylate 12.6copolymer Triethyl citrate 2.52 Glyceryl monostearate 0.95 Polysorbate80 0.13 Water 83.8

A total of 1300 grams of the particles obtained in Stage II were addedto the fluid bed equipment, previously heated to 35° C., and they werecoated with 4336 grams of the above suspension maintaining thetemperature between 25 and 28° C. throughout the process. Using a 590 μmsieve the agglomerates formed in the process were discarded, finallyobtaining omeprazole pellets, protected by the dibasic amino acid,isolated with a layer of methylcellulose and gastro-resistantcomponents.

The product revealed good analytical results in a pH 4.5 medium for 45minutes and the capacity to release said inhibitor at pH 6.8 in no morethan 45 minutes according to the assay described in BP 2012 Vol. III.

Stage IV: Drying the particles with internal and external protectionobtained in Stage III and size selection.

The particles obtained in Stage III were dried to humidity lower than 1%in the same fluid bed equipment, using a temperature of 40° C.

Using a sieving tower (Zonytest) the particle size distribution wasdetermined. It was observed that 92% of the particles were sized between350 and 500 microns. The particles sized over 590 microns (approximately5%) were eliminated.

Analytically, it showed:

1) That the omeprazole content per unit of weight of the pellets withrelative humidity below 1% obtained, was 23.4%.

2) Taking a sample before drying, it was shown that when the humiditycontent is over 1% the breakdown speed of the omeprazole contained inthe pellets is accelerated vis-à-vis the temperature and the existenceof related substances increases.

3) That the pellets obtained fulfilled the gastro-resistancy anddissolution assays described in BP 2012 Vol. III.

-   -   It was shown that in Stage II effective isolation was obtained        with a weight gain expressed in hydroxypropyl methylcellulose        over 19%.

4) That the particles fulfilled the related substance assays describedin USP 32, page 3426.

5) Accelerated thermal stress assay:

-   -   It was revealed that the omeprazole pellets with humidity below        1% obtained and preserved at 60° C. for 10 days do not have a        significant reduction in titration value and little increase in        the value found with related substances (0.6%).    -   In equal conditions commercially available pellets with an        average particle size range used as references revealed a        reduction in the omeprazole content of about 2.3% and an        increase in the related substances of about 3.2%, confirming the        advantages of the procedure described.    -   As the methacrylic acid and ethyl methacrylate copolymer,        Eudragit L30 D55 can be used.

Pellets were obtained with humidity below 1% and an omeprazole contentbetween 20 and 24%.

Example V: Preparing Enteric-Coated Pellets Containing Omeprazole onPure Cellulose Core and Aqueous Enteric Coating (Alternative Procedureto Example IV with the Addition of Talcum and Titanium Dioxide)

Starting with pure cellulose (100%) neutral cores with an average sizebetween 150 and 300 microns and with successive stages of bottom spraycoating, omeprazole enteric-coated pellets were obtained.

Microparticles of omeprazole previously protected by a dibasic aminoacid and isolated with a cover of hydroxypropyl methylcellulose werecoated with an aqueous enteric coating suspension, obtaining pelletssized between 350 and 500 μm and with a high omeprazole content.

The preparation was carried out in four independent stages each onefulfilling specific functions. They were:

Stage I: coating cellulose cores with a hydroalcoholic suspensioncontaining dissolved omeprazole and a dibasic amino acid in anethanol-water mixture (90/10); the suspension being formed by addingtalcum and subsequently the agent inhibiting the recrystallisation(polyvinylpyrrolidone) of the dibasic amino acid and homogenisation, isadded.

Stage I was carried out according to Example I with the same formula andprocess conditions.

Stage II: Isolating the particles obtained in Stage I.

It was carried out with the same formula, preparation and processconditions used in Stage II of Example I.

Stage III: Aqueous enteric coating of the particles obtained in StageII.

An aqueous suspension of C Type methacrylic acid copolymer (USP/NF) wasprepared according to

TABLE 1 composition of the enteric coating suspension. Raw materialGrams/100 g. de suspension Methacrylic acid and ethyly methacrylate 11.7copolymer Triethyl citrate 2.0 Glyceryl monostearate 0.7 Polysorbate 800.1 Talcum 0.6 Titanium dioxide 0.6 Water 84.1

THe formulation in Table 1:

A total of 5650 grams of the particles obtained in Stage II were addedto a fluid bed and 22658 grams of suspension were added, previouslyheating the equipment to 35 degrees, finally obtaining omeprazolepellets, protected by the dibasic amino acid, isolated with a cover ofhydroxypropyl methylcellulose and gastro-resistant products.

The product revealed good results in a pH 4.5 medium for 45 minutes andthe capacity to release said inhibitor at pH 6.8 in no more than 45minutes according to the assay described in BP 2012 Vol. III.

Stage IV: Drying the particles with internal and external protectionobtained in Stage III and size selection.

The particles obtained in Stage III were dried to humidity lower than 1%in the same fluid bed equipment, using a temperature of 40° C.

Using a sieving tower (Zonytest) the particle size distribution wasdetermined. It was observed that 92% of the particles were sized between350 and 500 microns. The particles sized over 590 microns (approximately5%) were eliminated.

Analytically, it was revealed:

1) That the omeprazole content per unit of weight of the pelletsobtained was 20.4% and their relative humidity was lower than 0.7%.

2) That a humidity content over 1% accelerates breakdown of theomeprazole contained in the pellets obtained and increases the existenceof related substances.

3) That the pellets obtained fulfilled the gastro-resistancy anddissolution assays described in BP 2012 Vol. III.

-   -   It was revealed that in Stage II effective isolation is obtained        with a weight gain expressed in hydroxypropyl methylcellulose        over 19%.

4) That the particles fulfilled related substance assays described inUSP 32, page 3426. and BP 2012 Vol. III.

With the procedure described above pellets were obtained with humiditylower than 1% and an omeprazole content between 20.0% and 24.0%.

Example VI—Preparing Oral Dispersion Tablets (ODT) Using PelletsContaining Omeprazole Over Pure Cellulose Cores and with Aqueous EntericCoating in a Sufficient Amount for a 20 mg Dosage

Starting with the omeprazole enteric-coated pellets described in ExampleIV, oral dispersion tablets were obtained by direct compression. Theformula is made up of approximately 30% of omeprazole pellets and 70% ofexcipients for direct compression usually used in pharmacy. Thefollowing compositions were prepared:

TABLE 1 Composition of the oral dispersion tablets, Formula A Formula B% of each % of each Raw material component component Omeprazole pellets(sufficient amount for a 28.5 30.2 20 mg/unit dosage) Pharmaburst 500(*) 60.3 43.8 Crosslinked Povidone 3.0 5.0 Colloidal anhydrous silicon0.5 0.5 Citric Acid 3.0 3.0 Lime-Lemon Essence 2.0 0 Peppermint essence0 4.0 Sucralose 1.7 2.5 Microcrystalline cellulose 0 10.0 Sodium StearylFumarate 1.0 1.0 (*) Pharmaburst: coprocessed product made up ofmannitol, sorbitol, maltitol, crospovidone, copovidone and silicondioxide.

The preparation was carried out in three independent stages. These were:

Stage I: Mixing the omeprazole pellets and the excipients.

-   -   All the excipients, except the lubricant (sodium stearyl        fumarate), were sieved with a 25 mesh sieve, to remove        agglomerates. Then they were added to a suitably sized conical        mixer, together with the omeprazole pellets and mixed for 20        minutes at 80 rpm.

Stage II: Lubricating the mixture.

The sodium stearyl fumarate was first passed through a 35 mesh sieve, itwas added to the mixer containing the mixture obtained in Stage I andmixed for 5 minutes at 80 rpm.

Stage III: Compressing the final mixture.

To compress the mixture a Piccola compressor was used with 4 punches.Samples were obtained in 2 different formats, round with a 9 mm diameterand square with 10 mm sides. Compression strengths of 5.5 KN, 7.5 KN and10.5 KN were used for the round format and 6.1 KN, 9.1 KN and 13.0 KNfor the square format. All at a unit weight of 350 mg. The mixturerevealed good flow and compactability throughout the process in allcases.

Controls applied to each simple obtained:

The samples obtained in Stage III with different compression strengthswere subjected to the following controls:

1) Control of weight uniformity, hardness, thickness and diameter.

2) Friability test (acc. to USP 32).

3) Disintegration control.

All the samples showed a variation in individual weight less than 5.0%and less than 2.5% in the average weight. For formula A in round format,the average hardnesses of each sample were 2.7 SC, 6.7 SC and 10.8 SCfor the strengths of 5.5 KN 7.5 KN and 10.5 KN respectively. The tabletthicknesses were 4.2 mm, 3.9 mm and 3.8 mm with respect to the samplesobtained with an increasing compression strength. For formula B insquare format, the average hardnesses of each sample were 3.3 SC, 5.6 SCand 7.0 SC for the strengths of 6.1 KN, 9.1 KN and 13.0 KN respectively.The tablet thicknesses were 4.9 mm, 4.8 mm and 4.6 mm with respect tothe samples obtained with an increasing compression strength.

In the first case, the samples obtained at 7.5 KN and 10.5 KN hadfriability values below 0.5% and a good appearance at the end of thetest. However, the sample of tablets obtained at 5.5 Kn had friabilityvalues greater than 0.5% and therefore, they were discarded. For thesquare format and formula B, all the samples obtained had friabilityvalues less than 0.5% and a good appearance.

The disintegration time in water, for formula A and the round format,was 6 seconds for the 5.5 KN strength, 12 seconds for the 7.5 KNstrength and 20 seconds for the 10.5 KN strength. For formula B and thesquare format, the times of 12 seconds, 18 seconds and 20 seconds wereobtained with an increasing compression strength.

Analytical Controls

The controls carried out were: assessment of the omeprazole content,uniformity of the unit dose, gastro-resistancy and dissolution testsdescribed in BP 2012 Vol. III.

In this example it was shown that starting with the microparticlesobtained in Example IV (omeprazole microparticles, protected by adibasic amino acid, isolated with a layer of hydroxypropylmethylcellulose and coated with an aqueous enteric coating suspension,with a final size between 350 and 500 μm) it is possible to obtain oraldispersion tablets.

The procedure described allows for preparing oral dispersion tablets forthe dosages of 10 and 40 mg of omeprazole compressed at a unit weight of175 mg and 700 mg respectively.

With procedures similar to this one, oral dispersion tablets wereobtained starting with:

a) Omeprazole microparticles, protected by a dibasic amino acid,isolated with a layer of hydroxypropyl methylcellulose and coated withan enteric coating of hydroalcoholic suspension, with a final sizebetween 500 and 710 μm (described in Example III).

b) Omeprazole microparticles, protected by a dibasic amino acid,isolated with a layer of hydroxypropyl methylcellulose and coated withan enteric coating of hydroalcoholic suspension, with a final sizebetween 420 and 590 μm (described in Example I and II).

-   -   In all cases the disintegration time in the buccal cavity was        less than 30 seconds and preferably less than 15 seconds.    -   In a similar way oral dispersion tablets were prepared,        containing indistinctively: esomeprazole and omeprazole with 10        or 40 mg.

Example VII—Preparing Capsules with Enteric Omeprazole Microparticles ina Sufficient Amount for a 20 mg Dosage of Active Ingredient

Starting with the enteric omeprazole pellets described in the examplesabove, a sufficient amount of microparticles was metered into rigidgelatine capsules to obtain a 20 mg dose of pure omeprazole activeingredient per capsule.

When Choosing the Size of the Capsule, the Following was Considered:

a) that the new size of the enteric-coated pellets obtained issignificantly smaller than the commercially available enteric-coatedpellets that have an average diameter of 1000 microns or more.

b) That the omeprazole content in the enteric-coated pellets accordingto the various examples above was greater than that in the commerciallyavailable enteric-coated pellets.

-   -   Specifically the pellets obtained in the corresponding examples        showed:

Cellulose Pellets cores Enteric coating AVERAGE (diameter (Stage III)SIZE Example (microns)) (medium) OMEPRAZOLE microns I 150/300Hydroalcoholic 12.6% 420/590 II 150/300 Hydroalcoholic 15.0% 420/590 III300/500 Hydroalcoholic 10.6% 500/710 IV 150/300 Aqueous 23.4% 350/500 V150/300 Aqueous 20.4% 350/500

c) the pellets with a content higher than 10.5% were chosen, andpreferably the pellets with a content higher than 12.0% by weight.

d) 20 mg. omeprazole expressed in active ingredient showed that they canbe added to smaller size capsules than those usually used (No. 2) andcommercially available.

Procedure:

The microparticles obtained were metered into rigid coni-snap gelatinecapsules, white and yellow in colour. A Zuma Brand encapsulating machinewas used with manual filling.

A total of 200 capsules were made with the enteric-coated pellets fromeach of the examples mentioned.

-   -   With the enteric-coated pellets prepared according to Examples        IV and V, empty capsules as small as possible and industrially        available were filled. Particularly, capsules No. 5.    -   In all cases the capsules containing 20 mg of omeprazole in the        form of pellets according to this invention were smaller than        the commercial available capsules with 20 mg omeprazole.

The following checks were made on the prepared capsules:

-   -   Filling uniformity (using average weight), variation less than        2.5%.    -   Individual weight, with variation less than 5%.    -   Average weight: 98.04 mg (95.59-100.49).    -   Individual weight: 98.04 mg (93.14-102.94).

Comparison with Capsules of Commercial Products with Equal Content:

Using commercial products as a reference and particularly, those calledUlcozol 20 mg. (by Laboratorios Bagó S.A.) and Buscasan 24 (byLaboratorios Boheringer Ingelheim) which also contain 20 mg. ofomeprazole in the form of enteric-coated pellets, it was observed thatthey are placed inside capsule No. 2 that is bigger than the capsulesobtained in this example (capsules No. 5).

The smaller size of the capsules (No. 5, 4 ó 3) that can be preparedwith the new enteric-coated pellets according to this inventiondetermine the following practical advantages:

1) Less input and cost during the primary packaging of the capsules inaluminium-aluminium blisters. Significant industrial advantage.

2) More easily swallowed by patients.

-   -   20 volunteers received normal size commercial capsules with 20        mg of omeprazole and also smaller size capsules containing 20        mg. of omeprazole according to this example. They all preferred        the smaller capsules.

3) In 20 healthy volunteers another possibility of use was revealed.That is, opening the capsule and pouring its content into liquids orfoods and then swallowing them. The small size of the enteric-coatedpellets did not cause discomfort when administered.

-   -   Both alternatives (swallowing complete small size capsules or        the powder from the capsules) revealed their practicality in        patients and particularly, patients with swallowing        difficulties.    -   Capsules containing 10 and 40 mg of omeprazole were also filled.    -   The characteristics mentioned are a direct consequence of the        small size and high content of the omeprazole pure active        ingredient contained in the enteric-coated pellets prepared        according to the examples described above.

Example VIII—Preparing Powder for Oral Suspension that ContainsOmeprazole Pellets, Prepared Over Pure Cellulose Cores and with anAqueous Enteric Coating

Starting with the enteric-coated omeprazole pellets described in Example4 sized between 350 and 500 microns and with an omeprazole content over20.0%, a powder mixture for oral suspension was obtained, which wasmetered into sachets, with a sufficient quantity for a dosecorresponding to 20 mg of omeprazole pure active ingredient.

The formula is made up of approximately from 2% to 3% of omeprazolepellets, 20% of a viscous agent that provides stability to thesuspension, 4% of citric acid which gives slight acidity to thesuspension protecting the enteric nature of the pellets, 70% of sugarand flavourings commonly used in pharmacy. The following formulae wereprepared:

TABLE 1 Composition of the power mixture for oral suspension Formula AFormula B % of each % of each Raw material component componentOmeprazole pellets (sufficient amount for a 3.3% 2.1% 20 mg/unit dose)Sucralose 0.8% 0.8% Lemon essence 0.7% Orange essence 0.7%  0% Creamessence 0.7%  0% Masking flavor 0 0.7% Citric acid 4.0% 4.0%Microcrystalline celluose and Sodium 20.0% 20.1%  carboxymethylcellulose Sugar 70.5% 71.8% 

The preparation was carried out in two independent Stages. These were:

Stage I: Mixing the excipients.

All the excipients, except the sugar, were sieved using a 25 mesh sieve,to remove the agglomerates therefrom. Then they were added to a suitablysized conical mixer, together with the corresponding amount of sugar andmixed for 15 minutes at 80 rpm.

Stage II: Metering.

Metering was carried out using a sachet filling machine with two feedingstations. The mixture of excipients was metered in the first station,and the enteric-coated omeprazole pellets in the second. The supply toeach station was calibrated beforehand, each independently from theother, so that the amount of pellets metered per sachet was thesufficient amount for a 20 mg dose of omeprazole, and the amount ofexcipients metered in the first station was the sufficient amount toobtain a final content of 5 grams per sachet.

The material of the sachet used was a suitable aluminium sheet thatenables protecting the product from light and ambient humidity.

Controls Carried Out on Each Sample Obtained:

The samples obtained in Stage II were subjected to the followingcontrols:

1) Control of weight uniformity. By emptying the contents of eachmetered dose only with the enteric-coated omeprazole pellets.

2) Control of weight uniformity. By emptying the contents of each doseonly with the excipient mixture.

3) Control of weight uniformity. By emptying the content of each finalunit.

4) Airtightness control

5) Visual appearance control.

All the samples had an individual weight variation lower than 5.0% andlower than 2.5% in the average weight.

Analytical Controls

The controls carried out were: assessment of the omeprazole content,uniformity of unit dose, gastro-resistance and dissolution assaysdescribed in BP 2012 Vol. III.

The following were prepared with the same formulas described previouslyand modifying the metering per unit in a proportional way:

a) powder for suspension in sachets containing 10 and 40 mg ofomeprazole per dose unit, at a final weight of 2.5 g and 10 grespectively.

b) powder for suspension packaged in single and multiple dose vials thatprovide per dose unit 10, 20 or 40 mg. of omeprazole respectively.

-   -   Swallowing the powder reconstituted with water, originating from        sachets or vials and with a different omeprazole content, at no        time caused swallowing problems among the volunteers who took        the respective suspensions thanks to the size of the pellets        containing said powder.    -   In all cases, the reconstituted powder was well accepted.

Example IX—Sugar-Free Powder for Suspension

It was prepared according to Example VIII above, with the omeprazolepellets with a pure cellulose (100%) core and following Stages I and IIdescribed above, but eliminating the sugar mentioned in Table 1 above,and increasing up to 5.0% the percentage of sucralose quoted in saidTable.

The sucralose added as a sweetener is practically not absorbed, and itdoes not alter the blood glucose levels, as is known and described inthe bibliography.

The sucralose's behaviour, together with the pure cellulose cores freeof described sugars, determines that the preparation in powder form forsuspension is particularly beneficial for patients with diabetes

Example X: Pharmaceutical Composition Containing Omeprazole Pellets inAssociation with Microcapsules of Sodium Diclofenac

The enteric-coated pellets prepared as described in Example IV and sizedbetween 350 and 500 microns and with a high omeprazole content wereassociated with enteric-coated sodium diclofenac microcapsules.

The diclofenac microcapsules were prepared previously as described inthe international patent application published under number WO2013/139377 A1 by the same applications as this invention.

The prepared associations contain 25 to 100 mg of microencapsulated andenteric-coated sodium diclofenac and between 10 and 40 mg of omeprazolepellets.

The following were prepared:

a) Oral disintegration tablets (ODT) according to the proceduredescribed in Example IV.

b) Capsules, according to the procedure described in Example VII. Inthis case the chosen capsules were size 4.

c) Powder for oral suspension, according to Example VIII.

In all cases, the preparation was carried out with the same excipientsand procedures mentioned in each example. To the mixtures described ineach example the diclofenac microcapsules were added in an amountbetween 25 and 100 mg of sodium diclofenac, previously corrected bytitration value.

The compositions obtained had a greater weight than those mentioned foreach composition in Examples IV, VII and VIII but there physicalcharacteristics were similar.

1. A pharmaceutical composition, comprising: enteric-coated pelletshaving an average diameter between 350 and 710 microns, theenteric-coated pellets comprising: pure cellulose cores, wherein thecores have a particle size range between 150 and 500 microns, a coatingdisposed on the pure cellulose cores, the coating containing each of: aproton pump inhibitor with benzimidazole structure in an amount greaterthan 10.5% by weight with respect to the total weight of theenteric-coated pellets, a dibasic amino acid selected from the groupconsisting of lysine, histidine and L-arginine, andpolyvinylpyrrolidone, wherein the dibasic amino acid is present in anamount less than or equal to 10% by weight in relation to the weight ofthe proton pump inhibitor, and an enteric coating disposed over saidcoating, wherein enteric-coated pellets that contain pure cellulosecores having an average diameter between 150 and 300 microns have anaverage diameter between 350 and 590 microns and enteric-coated pelletsthat contain pure cellulose cores with an average diameter between 300and 500 microns have an average diameter between 500 and 710 microns. 2.The pharmaceutical composition according to claim 1, wherein theenteric-coated pellets are present in an amount of 20 to 35% by weight,with respect to the total weight of the pharmaceutical composition,wherein the pharmaceutical composition further comprises one or morepharmaceutically-acceptable excipients, and wherein the pharmaceuticalcomposition is an oral disintegration tablet.
 3. The compositionaccording to claim 2, wherein the oral disintegration tablet has adisintegration time in a buccal cavity of less than 30 seconds.
 4. Thepharmaceutical composition according to claim 1, wherein theenteric-coated pellets are present in an amount between 2 and 4% byweight, with respect to the total weight of the pharmaceuticalcomposition, wherein the pharmaceutical composition further comprises:between 10 and 30% by weight, of a mixture of microcrystalline celluloseand carboxymethyl cellulose; between 2 and 6%, of citric acid; and atleast one flavoring, wherein the pharmaceutical composition is a powderformulated for oral suspension.
 5. The pharmaceutical compositionaccording to claim 1, wherein the enteric-coated pellets are disposed ina gelatin capsule smaller than capsule size No.
 2. 6. The pharmaceuticalcomposition according to claim 1, wherein the pharmaceutical compositioncomprises 10, 20 or 40 mg of the proton pump inhibitor.
 7. Thepharmaceutical composition according to claim 1, formulated as a singleor multiple dose pharmaceutical composition.
 8. The pharmaceuticalcomposition according to claim 1, further comprising enteric-coatedmicrocapsules of diclofenac.
 9. The pharmaceutical composition accordingto claim 8, wherein the proton pump inhibitor is present in an amount inthe range of 10 to 40 mg and the diclofenac is present in an amount inthe range of 25 to 100 mg.
 10. The pharmaceutical composition accordingto claim 8, wherein the proton pump inhibitor is omeprazole oresomeprazole.